Rejected drug may help treat Alzheimer's, Parkinson's diseases

Postdoctoral fellow part of team to publish new study in Molecular Psychiatry

Aug. 22, 2012

An international team of scientists that includes a postdoctoral fellow at Brandeis has found a previously-rejected compound may be helpful in treating neurodegenerative conditions like Alzheimer’s and Parkinson’s disease.

The team, which includes Shulin Ju, Ph.D., a postdoctoral fellow under the direction of molecular biology professors Gregory Petsko and Dagmar Ringe, found that the compound latrepiridine, known commercially as Dimebon, reduced the level of at least two neurodegeneration-related proteins in mice.

The second of two studies, published this month in Molecular Psychiatry, demonstrates new potential for this compound in the treatment of Alzheimer’s disease, Parkinson’s disease, sleep disorders and other neurodegenerative conditions.

In the 1990s, latrepiridine appeared effective in treating some of the earliest animal models of Alzheimer’s disease. In a high profile Phase II clinical trial in Russia, overseen by a panel of top U.S. clinical trialists, latrepirdine showed significant and sustained improvement in cognitive behavior in Alzheimer’s patients with minimal side effects. But it did not demonstrably improve the condition of patients in a Phase III trial in the United States, causing the sponsors to halt further clinical study.

Before the failed trials however, Mount Sinai School of Medicine researchers led by Sam Gandy, director of the Mount Sinai Center for Cognitive Health, began studying how latrepirdine worked. John Steele, a Mount Sinai neuroscience graduate student, devoted his thesis to these studies. Lenard Lachenmayer, a postdoctoral fellow working under the supervision of Zhenyu Yue, associate professor of neurology at Mount Sinai, shares first authorship of the new paper with Steele and with Ju.

In the new study, the researchers administered the drug to three different systems: yeast, mice and mammal cells, all showing build-up of alpha-synuclein, a protein known to cause neurodegeneration. In all three systems, they determined that latrepiridine activated autophagy, the so-called “self-eating” process of cells that protects the brain from neurodegeneration, which targeted synuclein and protected against its toxicity. In mice, the drug reduced the amount of synuclein accumulated in the brain through autophagy.